Synthetic agents in the context of metabolic/bariatric surgery: expanding the scope and impact of diabetes drug discovery

Abstract

Type 2 diabetes (T2D) --particularly with concurrent obesity ('diabesity') --is an intensifying global public-health problem. Medical needs and market opportunities in the T2D space have propelled discovery efforts aimed at inventing new synthetic T2D drugs differentiable by improved safety and efficacy and/ or the ability to modulate emerging T2D targets. Particularly for moderately and severely obese individuals, weight-loss (bariatric) surgery offers an effective means of reducing obesity-driven T2D that is superior in many respects to medical T2D management. Yet, not all overweight or obese individuals with T2D qualify for bariatric surgery, and current healthcare resources are inadequate for applying surgical T2D control to more than a very small segment of qualified patients. Bariatric surgery is no guarantee of 'curative' T2D abrogation, significant rates of T2D non-remission or re-emergence having been observed in diabesity patients following bariatric procedures. Preoperative glucose control by oral hypoglycemic drugs reduces the chance of T2D recurrence post-surgery, and diabesity patients in whom glycemic indices have been improved by bariatric surgery may still require some level of T2D pharmacotherapy. Laboratory and clinical data indicate that synthetic T2D drugs can improve T2D-related outcomes following bariatric procedures, and current T2D drug-discovery efforts are being informed by the metabolic advantages associated with bariatric surgery. These circumstances intensify the need for and extend the impact of T2D drug discovery by demonstrating multiple levels of interplay between medical and surgical approaches to improve the health of individuals with diabesity and, perhaps, approach the overarching goal of decreasing long-term cardiovascular mortality.Keywords: cardiovascular risk, diabesity, endocrine disease, glycemic control, insulin resistance, metabolic syndrome, obesity, vascular disease Expert Opin. Drug Discov. (2014) 9(3):221-228 BackgroundIn the November, 2013, issue of Expert Opinion on Drug Discovery, Safavi et al. [1] surveyed approved synthetic drugs and late-stage pipeline compounds as pharmacotherapeutics for type 2 diabetes (T2D). Concluding that 'finding new targets and ... synthetic methods' is the 'main goal in T2D drug discovery,' the authors mention in passing that weight-loss (bariatric) surgery 'is a highly effective treatment for obesity-related T2D.' This commentary aims to widen the aperture afforded by Safavi and colleagues by considering the proposition that the inability of bariatric surgery to eradicate the T2D pandemic expands the scope of and presents new opportunities for drug discovery in the T2D space. 221All rights reserved: reproduction in whole or in part not permitted 2. Bariatric surgery can effectively address, but has not solved, the T2D problemAn intensifying worldwide epidemic, obesity contributes to the development of numerous disabling and lifespan-limiting maladies. One of these, T2D, is well recognized as obesity's principal metabolic comorb...

Novel Insight into the Mechanism of Metabolic Surgery Causing the Diversity in Glycemic Status in Type 2 Diabetes

“…While partial and total remission rates are high for patients with T2D undergoing metabolic surgery, the beneficial efficacy is not attained in all individuals. Swedish Obese Subjects (SOS) and other clinical trials demonstrated that 20 % to over 40 % of patients did not have T2D remission within 1-2 years post-procedure [14,16] and this value was 11.3 % for 5-year follow-up after RYGB [17]. These patients remain in a hyperglycemic state and need pharmacotherapy [18].…”